Mutations in KATNB1 Cause Complex Cerebral Malformations by Disrupting Asymmetrically Dividing Neural Progenitors

Abstract

In the original Figure 5 legend the 3D projections of Z sections and quantifications of glial cells were mislabeled. This has been corrected in the article online.228 Neuron 85, 228, January 7, 2015 ª2015 Elsevier Inc.

Mutations in the Katnb1 gene cause left–right asymmetry and heart defects

“…Such defects are consistent with defects in left-right pathway genes, including the main effector of the Nodal pathway, the transcription factor Pitx2 (Kitamura et al, 1999;Lu et al, 1999;Furtado et al, 2011). Katnb1 -/embryos also displayed severe growth retardation and neural tube defects as previously described (Hu et al, 2014;Mishra-Gorur et al, 2014), once again consistent with various ciliopathy syndromes (Lorda-Sanchez et al, 2000;Louie and Gleeson, 2005;Ferrante et al, 2006;Tobin and Beales, 2007;Harris and Torres, 2009;Lancaster and Gleeson, 2009;Leigh et al, 2009;Bataille et al, 2011;Norris and Grimes, 2012;Hoff et al, 2013;Onoe et al, 2013). Although Katnb1 -/embryos could not be found at late fetal stages, the allelic series (Katnb1 -/Taily ) used in this study allowed us to investigate heart formation at later developmental time points, when heart morphogenesis is complete.…”

“…Katnb1 expression has been previously reported in the murine and human testis (O'Donnell et al, 2012;Pleuger et al, 2016), cerebral cortex during mouse, human, and zebrafish development (Hu et al, 2014;Mishra-Gorur et al, 2014) and developing heart (Yu et al, 2005). Due to the insertion of a beta-galactosidase reporter cassette in our Katnb1 recombination locus, we were able to detect LacZ activity in Katnb1 1/embryos ( Figs.…”

“…Of interest, mouse genetic models have been proved useful to detect partially penetrant phenotypes not always obvious in patient screenings (Norris and Grimes, 2012), and we believe this to be the case for the Katnb1 gene. Previous mutation screenings have identified a role for KATNB1 in brain development in humans (Hu et al, 2014;Mishra-Gorur et al, 2014), but have not explored heart formation. While we would predict severe heart defects in humans containing the equivalent genetic variants, as for all syndromic ciliopathies, phenotype penetrance is variable (Hu et al, 2014;Mishra-Gorur et al, 2014).…”

“…While the katanin KATNA1 subunit displays catalytic activity and is the effector protein within the complex, KATNB1 serves to modestly enhance severing activity, but more importantly define severing specificity (Hartman and Vale, 1999;Roll-Mecak and McNally, 2010). N-Terminal and missense mutations, as well as loss of function of KATNB1 in patients are causative of cerebral malformations, presumably through limiting centriole and cilia number (Hu et al, 2014), disruption of mitotic spindle formation and consequent neuroblast formation and dendritic arborization (Mishra-Gorur et al, 2014), but the role of KATNB1 in cardiovascular abnormalities is so far unexplored.…”

A 16q12.2q21 deletion identified in a patient with developmental delay, epilepsy, short stature, and distinctive features

“…Fifteen of those genes are registered as OMIM genes (Online Mendelian Inheritance in Man; http://omim.org/), thus suggesting a relationship between these genes and phenotypic features. Among them, the katanin p80 (WD repeat containing) subunit B 1 gene (KATNB1) is the gene responsible for lissencephaly 6, with microcephaly (MIM#616212) (Mishra-Gorur et al 2014). The Bardet-Biedl syndrome 2 gene (BBS2) is related to Bardet-Biedl syndrome (MIM#615981).…”